title: Targeted silencing of DNA-specific B cells combined with partial plasma cell depletion displays additive effects on delaying disease onset in lupus-prone mice.
abstract: Targeting autoreactive B lymphocytes at any stage of their differentiation could yield viable therapeutic strategies for treating autoimmunity. All currently used drugs, including the most recently introduced biological agents, lack target specificity. Selective silencing of double-stranded DNA-specific B cells in animals with spontaneous lupus has been achieved previously by the administration of a chimeric antibody molecule that cross-links their DNA-reactive B cell immunoglobulin receptors with inhibitory FcγIIb (CD32) receptors. However, long-lived plasmacytes are resistant to this chimeric antibody as well as to all conventional treatments. Bortezomib (a proteasome inhibitor) depletes most plasma cells and has been shown recently to suppress disease activity in lupus mice. We hypothesized that the co-administration of non-toxic doses of bortezomib, that partially purge long-lived plasma cells, together with an agent that selectively silences DNA-specific B cells, should have additive effects in an autoantibody-mediated disease. Indeed, our data show that the simultaneous treatment of lupus-prone MRL/lpr mice with suboptimal doses of bortezomib plus the chimeric antibody resulted in the prevention or the delayed appearance of the disease manifestations as well as in a prolonged survival. The effect of the combination therapy was significantly stronger than that of the respective monotherapies and was comparable to that observed after cyclophosphamide administration.
authors.affiliation: Department of Immunology, Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: K A
authors.initials: KA
authors.lastname: Nikolova-Ganeva
authors.forename: V V
authors.initials: VV
authors.lastname: Gesheva
authors.forename: T A
authors.initials: TA
authors.lastname: Todorov
authors.forename: R E
authors.initials: RE
authors.lastname: Voll
authors.forename: T L
authors.initials: TL
authors.lastname: Vassilev
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism*; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D003520:Cyclophosphamide / Q000008:administration & dosage; D004247:DNA / Q000737:chemistry; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000628:therapy*; D008212:Lymphocyte Depletion; D051379:Mice; D019463:Mice, Inbred MRL lpr; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000008:administration & dosage; D017452:Receptors, IgG / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D001324:Autoantigens; D001897:Boronic Acids; C499172:Fcgr2b protein, mouse; D010446:Peptide Fragments; D011719:Pyrazines; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D000069286:Bortezomib; D003520:Cyclophosphamide; D004247:DNA
keywords: SLE; autoimmunity; autoreactive B cells; plasmacytes